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Background: Hepatopulmonary syndrome (HPS) is characterized by an arterial oxygenation defect, defined by an increased alveolar-arterial oxygen gradient, induced by pulmonary vascular dilatations in the context of liver disease. The pathogenesis of HPS is poorly understood. Morphologic changes associated with HPS are unknown. This study aimed at describing imaging and pathology changes associated with HPS.Methods: We performed a case-control study in candidates for transplant with suspicion of cirrhosis. Each patient with HPS (Pao2 ≤ 70 mm Hg) was matched to three control subjects for age, cause, and liver disease severity. Pretransplant thoracic and abdominal imaging and explanted livers were reviewed.Results: CT scans and Doppler ultrasounds from 21 patients with HPS were compared with those from 63 control subjects. HPS was associated with a two- to threefold higher prevalence of obstructed intrahepatic portal branches, of slowed or hepatofugal portal blood flow, and of large abdominal portosystemic shunts. Hepatic artery diameter was also larger in patients with HPS. Explanted livers from 19 patients with HPS were compared with those from 57 control subjects. HPS was associated with a fourfold higher prevalence of portal venule thrombosis and a ninefold higher prevalence of extensive vascular proliferation within fibrous septa. Obstruction of centrilobular venules, sinusoidal dilatation, and liver parenchymal extinction were also more common in patients with HPS.Conclusions: HPS is associated with intrahepatic vascular changes and with features suggesting severe portal hypertension. These results raise the hypothesis that intrahepatic vascular changes precipitate the development of HPS, opening new therapeutic perspectives for HPS. [ABSTRACT FROM AUTHOR]

Importance: Prednisolone or pentoxifylline is recommended for severe alcoholic hepatitis, a life-threatening disease. The benefit of their combination is unknown.Objective: To determine whether the addition of pentoxifylline to prednisolone is more effective than prednisolone alone.Design, Setting, and Participants: Multicenter, randomized, double-blind clinical trial conducted between December 2007 and March 2010 in 1 Belgian and 23 French hospitals of 270 patients aged 18 to 70 years who were heavy drinkers with severe biopsy-proven alcoholic hepatitis, as indicated by recent onset of jaundice in the prior 3 months and a Maddrey score of at least 32. Duration of follow-up was 6 months. The last included patient completed the study in October 2010. None of the patients were lost to follow-up for the main outcome.Intervention: Patients were randomly assigned to receive either a combination of 40 mg of prednisolone once a day and 400 mg of pentoxifylline 3 times a day (n=133) for 28 days, or 40 mg of prednisolone and matching placebo (n=137) for 28 days.Main Outcomes and Measures: Six-month survival, with secondary end points of development of hepatorenal syndrome and response to therapy based on the Lille model, which defines treatment nonresponders after 7 days of initiation of treatment.Results: In intention-to-treat analysis, 6-month survival was not different in the pentoxifylline-prednisolone and placebo-prednisolone groups (69.9% [95% CI, 62.1%-77.7%] vs 69.2% [95% CI; 61.4%-76.9%], P = .91), corresponding to 40 vs 42 deaths, respectively. In multivariable analysis, only the Lille model and the Model for End-Stage Liver Disease score were independently associated with 6-month survival. At 7 days, response to therapy assessed by the Lille model was not significantly different between the 2 groups (Lille model score, 0.41 [95% CI, 0.36-0.46] vs 0.40 [95% CI, 0.35-0.45], P = .80). The probability of being a responder was not different in both groups (62.6% [95% CI, 53.9%-71.3%] vs 61.9% [95% CI, 53.7%-70.3%], P = .91). The cumulative incidence of hepatorenal syndrome at 6 months was not significantly different in the pentoxifylline-prednisolone and the placebo-prednisolone groups (8.4% [95% CI, 4.8%-14.8%] vs 15.3% [95% CI, 10.3%-22.7%], P = .07).Conclusion and Relevance: In patients with alcoholic hepatitis, 4-week treatment with pentoxifylline and prednisolone, compared with prednisolone alone, did not result in improved 6-month survival. The study may have been underpowered to detect a significant difference in incidence of hepatorenal syndrome, which was less frequent in the group receiving pentoxifylline.Trial Registration: clinicaltrials.gov Identifier: NCT01214226. [ABSTRACT FROM AUTHOR]

IMPORTANCE Prednisolone or pentoxifylline is recommended for severe alcoholic hepatitis, a life-threatening disease. The benefit of their combination is unknown. OBJECTIVE To determine whether the addition of pentoxifylline to prednisolone is more effective than prednisolone alone. DESIGN, SETTING, AND PARTICIPANTS Multicenter, randomized, double-blind clinical trial conducted between December 2007 and March 2010 in 1 Belgian and 23 French hospitals of 270 patients aged 18 to 70 years who were heavy drinkers with severe biopsyproven alcoholic hepatitis, as indicated by recent onset of jaundice in the prior 3 months and a Maddrey score of at least 32. Duration of follow-up was 6 months. The last included patient completed the study in October 2010. None of the patients were lost to follow-up for the main outcome. INTERVENTION Patients were randomly assigned to receive either a combination of 40 mg of prednisolone once a day and 400 mg of pentoxifylline 3 times a day (n=133) for 28 days, or 40 mg of prednisolone and matching placebo (n=137) for 28 days. MAIN OUTCOMES AND MEASURES Six-month survival, with secondary end points of development of hepatorenal syndrome and response to therapy based on the Lille model, which defines treatment nonresponders after 7 days of initiation of treatment. RESULTS In intention-to-treat analysis, 6-month survival was not different in the pentoxifylline-prednisolone and placebo-prednisolone groups (69.9% [95% CI, 62.1%-77.7%] vs 69.2% [95% CI; 61.4%-76.9%], P = .91), corresponding to 40 vs42 deaths, respectively. In multivariable analysis, only the Lille model and the Model for End-Stage Liver Disease score were independently associated with 6-month survival. At 7 days, response to therapy assessed by the Lille model was not significantly different between the 2 groups (Lille model score, 0.41 [95% CI, 0.36-0.46] vs 0.40 [95% CI, 0.35-0.45], P = .80). The probability of being a responder was not different in both groups (62.6% [95% CI, 53.9%-71.3%] vs 61.9% [95% CI, 53.7%-70.3%], P = .91). The cumulative incidence of hepatorenal syndrome at 6 months was not significantly different in the pentoxifylline-prednisolone and the placebo-prednisolone groups (8.4% [95% CI, 4.8%-14.8%] vs 15.3% [95% CI, 10.3%-22.7%], P = .07). CONCLUSION AND RELEVANCE In patients with alcoholic hepatitis, 4-week treatment with pentoxifyiline and prednisolone, compared with prednisolone alone, did not result in improved 6-month survival. The study may have been underpowered to detect a significant difference in incidence of hepatorenal syndrome, which was less frequent in the group receiving pentoxifylline. TRIAL REGISTRATION clinicaltrials.gov Identifier: NCT01214226. [ABSTRACT FROM AUTHOR]

High plasma fibroblast growth factor-23 (FGF23) concentration predicts the risk of death and poor outcomes in patients with chronic kidney disease or chronic heart failure. We checked if FGF23 concentration could be modified in patients with end stage liver disease (ESLD) and predict mortality. We measured plasma FGF23 in 200 patients with ESLD registered on a liver transplant waiting list between January 2005 and October 2008. We found that median plasma FGF23 concentration was above normal values in 63% of the patients. Increased FGF23 concentration was not explained by its classical determinants: hyperphosphataemia, increased calcitriol concentration or decreased renal function. FGF23 concentration correlated with the MELD score, serum sodium concentration, and GFR. Forty-six patients died before being transplanted and 135 underwent liver transplantation. We analyzed the prognostic value of FGF23 levels. Mortality was significantly associated with FGF23 levels, the MELD score, serum sodium concentration and glomerular filtration rate. On multivariate analyses only FGF23 concentration was associated with mortality. FGF23 levels were independent of the cause of the liver disease. To determine if the damaged liver can produce FGF23 we measured plasma FGF23 concentration and liver FGF23 mRNA expression in control and diethyl-nitrosamine (DEN)-treated mice. FGF23 plasma levels increased with the apparition of liver lesions in DEN-treated mice and that FGF23 mRNA expression, which was undetectable in the liver of control mice, markedly increased with the development of liver lesions. The correlation between FGF23 plasma concentration and FGF23 mRNA expression in DEN-treated mice suggests that FGF23 production by the liver accounts for the increased plasma FGF23 concentration. In conclusion chronic liver lesions can induce expression of FGF23 mRNA leading to increased FGF23 concentration, which is associated with a higher mortality in patients on a liver-transplant waiting list. In these patients FGF23 concentration was the best predictor of mortality. [ABSTRACT FROM AUTHOR]

Purpose: To assess the effect of tezosentan, a parenteral dual ET receptor antagonist, on splanchnic and systemic hemodynamics in patients with cirrhosis. In addition, the safety, pharmacokinetics, and pharmacodynamics of tezosentan were evaluated. Methods: The population consisted of patients with cirrhosis with clinically significant portal hypertension. This was a randomized, double-blind, multicenter study. The patients were randomized 3:1 to tezosentan (3 mg/h for 2-3 h) or placebo. HVPG, hepatic blood flow (HBF, ICG method), and systemic arterial pressures were measured before and after tezosentan administration. Plasma concentrations of tezosentan and ET-1 were determined peripherally and in the hepatic vein. Results: Eighteen patients received tezosentan and six placebo. Baseline clinical, biochemical, and hemodynamic characteristics were balanced between the two groups. There was no significant treatment effect on HVPG. The extraction ratio (0.31), the plasma clearance of ICG (280 ml/min), and the HBF (1,430 ml/min) did not show any relevant changes during the infusion of tezosentan, and there were no differences between placebo- and tezosentan-treated patients. A linear relationship was observed between the maximum-fold increase in ET-1 concentration and the steady-state tezosentan plasma concentration ( r = 0.82). There was a strong correlation ( r = 0.88) between plasma clearance of ICG and that of tezosentan (10.2 l/h). Arterial pressure and heart rate did not significantly change in either group. Conclusion: In patients with cirrhosis, a 2- to 3-h tezosentan infusion was safe and well tolerated but did not change the HVPG. Tezosentan infusion had no influence on the extraction ratio and plasma clearance of ICG and did not change HBF. [ABSTRACT FROM AUTHOR]

Bacterial DNA (bactDNA) has been found in serum and ascitic fluid (AF) of 30-40% of hospitalized patients with cirrhosis and non-neutrocytic ascites, but its prevalence in outpatients is unknown. The aim of this prospective study was to investigate the presence of bactDNA in AF and serum among cirrhotic outpatients with non-neutrocytic ascites. Thirty-one consecutive patients with cirrhosis and non-neutrocytic ascites, who underwent therapeutic paracentesis in our outpatient clinic, were enrolled over a 13-week period. Of these patients, 13 had a single paracentesis and 18 patients had several consecutive paracenteses (2-10) over the study period. Overall, 98 serum and non-neutrocytic AF specimens were obtained and tested for the presence of bactDNA by polymerase chain reaction amplification of the 16S ribosomal RNA gene. The main causes of cirrhosis were alcohol (53.5%) and hepatitis C (30%). The median MELD score was 16 and there were 54.8% Child-Pugh C patients. BactDNA was negative in all samples from 28 of the 31 patients, including 15 patients with several paracentesis. One patient had a single AF sample culture positive and bactDNA positive for Streptococcus mitis, whereas the simultaneous blood sample was negative. For each of the last two patients, DNA from Lactococcus lactis was detected in a single blood sample but not in the simultaneous AF sample. In contrast to that reported previously in hospitalized patients, bactDNA is rarely detected in serum and AF of outpatients with cirrhosis and non-neutrocytic ascites. [ABSTRACT FROM AUTHOR]

In hepatocytes, the accumulation of unfolded proteins in the endoplasmic reticulum (ER) causes ER stress and the unfolded protein response (UPR), mediated by the ER-resident stress sensors ATF-6, IRE1, and PERK. UPR-responsive genes are involved in the fate of ER-stressed cells. Cells carrying hepatitis C virus (HCV) subgenomic replicons exhibit in vitro ER stress and suggest that HCV inhibits the UPR. Since in vivo ER homeostasis is unknown in livers with chronic HCV infection, we investigated ER stress and the UPR in liver samples from untreated patients with chronic hepatitis C (CHC), in comparison with normal livers. Electron microscopy, western blotting, and real-time RT-PCR were used in liver biopsy specimens. Electron microscopy identified features showing ER stress in hepatocyte samples from patients with CHC; however, 'ER-stressed' hepatocytes were found in clusters (3-5 cells) that were scattered in the liver parenchyma. Western blot analysis confirmed the existence of hepatic ER stress by showing activation of the three ER stress sensors ATF-6, IRE1, and PERK in CHC. Real-time RT-PCR showed no significant induction of UPR-responsive genes in CHC. In contrast, genes involved in the control of diffuse processes such as liver proliferation, inflammation, and apoptosis were significantly induced in CHC. In conclusion, livers from patients with untreated CHC exhibit in vivo hepatocyte ER stress and activation of the three UPR sensors without apparent induction of UPR-responsive genes. This lack of gene induction may be explained by the inhibiting action of HCV per se (as suggested by in vitro studies) and/or by our finding of the localized nature of hepatocyte ER stress. Copyright © 2010 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd. [ABSTRACT FROM AUTHOR]

Background/objective: Little is known on the morphological changes in the kidneys of cirrhotic patients with abnormal urinalysis and/or high serum creatinine levels. This retrospective, one-point-in-time study aimed to report the results of the analysis of renal biopsy specimens obtained in patients with cirrhosis. Methods: We retrieved information on 65 patients who underwent transvenous renal biopsy for proteinuria >0.5 g/day and/or microscopic haematuria and/or unexplained renal impairment (defined by serum creatinine levels >1.5 mg/dl). Results: Fifty-one per cent of the patients had proteinuria >0.5 g/day, 58% had haematuria and 83% had renal impairment. Renal biopsy disclosed injury to glomeruli in 77% of the patients, to vessels in 69% and to the tubulointerstitium system in 94% (chronic in 77%; acute in 75%). Fibrous endarteritis was the most common renal vascular lesion. Injuries to different structures were frequently combined. Isolated glomerular alterations were found in only two patients. Acute tubular necrosis was significantly more common in patients with fibrous endarteritis than in those without. Among 18 patients with renal impairment, proteinuria <0.5 mg/day and no haematuria, 10 had glomerular lesions, 13 had chronic tubulointerstitial lesions and 12 acute tubulointerstitial lesions. Conclusion: In patients with cirrhosis, various types of renal injuries are frequently combined. Chronic lesions (vascular or tubulointerstitial) may influence the outcome, in particular in patients who subsequently undergo liver transplantation and receive anticalcineurins. Renal vascular lesions may increase the risk of acute tubular necrosis. In patients with renal impairment, the absence of significant proteinuria and haematuria do not rule out the presence of renal lesions. [ABSTRACT FROM AUTHOR]

Aim: In patients with advanced cirrhosis, little is known about the ability of peripheral blood monocytes to spontaneously produce signaling proteins such as cytokines. The aim of this ex vivo study was to evaluate cytokine production under baseline conditions and after stimulation by lipopolysaccharide (LPS), a toll-like receptor (TLR) agonist. Methods: Peripheral blood monocytes were isolated from patients with advanced alcoholic cirrhosis (without ongoing bacterial infections) and normal subjects. Cells were left unstimulated or were stimulated with LPS. The abundance of 24 cytokines was measured using a filter-based, arrayed sandwich enzyme-linked immunosorbent assay (ELISA) in the supernatant of cultured monocytes. Results: Cirrhotic monocytes spontaneously produced six proteins (TNF-α, IL-6, IL-8, MCP-1, RANTES and Gro), whereas normal monocytes produced only small amounts of IL-8 and RANTES. Analyses with the online gene set analysis toolkit WebGestalt ( ) found enrichment for the six proteins in the human gene ontology subcategory ( ), Kyoto Encyclopedia of Genes and Genome pathways ( ) and BioCarta pathways ( ) consistent with a proinflammatory phenotype of cirrhotic monocytes resulting from activated TLR signaling. Interestingly, LPS-elicited TLR engagement further increased the production of the six proteins and did not induce the secretion of any others, in particular the anti-inflammatory cytokine IL-10. LPS-stimulated normal monocytes produced TNF-α, IL-6, IL-8, MCP-1, RANTES, Gro and IL-10. Conclusion: In patients with advanced cirrhosis, peripheral blood monocytes spontaneously produce proinflammatory cytokines, presumably in response to unrestricted TLR signaling. [ABSTRACT FROM AUTHOR]

Background/Aim: In cirrhosis, systemic nitric oxide (NO) overproduction and hepatic NO hypoproduction lead to arterial vasodilatation and portal hypertension. The mechanisms involved in these alterations in endothelial NO synthase (eNOS)-derived NO production in hepatic and systemic vasculature remain unknown. The aim of this study was to evaluate the regulation of eNOS and its major modulators in the liver and aorta during the development of cirrhosis in rats. Methods: Activated eNOS and Akt and expressions, and caveolin-1 (Cav-1) and scavenger receptor class B type I (SR-BI) expressions were measured before and 1, 2, 3 and 4 weeks after bile duct ligation. Plasma high-density lipoprotein (HDL) levels were measured. Results: Activated aortic eNOS increased at week 1, whereas it began to decrease at week 3 in the liver. Aortic expression of Cav-1 decreased at week 3 while hepatic expression increased by four-fold. Activated aortic Akt increased progressively while in the liver it gradually decreased during the development of cirrhosis. HDL levels decreased during the first week and decreased thereafter. The hepatic expression of SR-BI decreased. Conclusion: This study shows that the modulation of Akt and Cav-1 is inverted in the liver and the aorta during the development of cirrhosis. In addition, decreased HDL levels may play a role in reduced hepatic eNOS activity. [ABSTRACT FROM AUTHOR]

Type 1 hepatorenal syndrome (HRS) is prerenal failure specific to decompensated cirrhosis. In patients with HRS, there is marked splanchnic/systemic vasodilation resulting in arterial hypotension, arterial baroreceptor unloading, overstimulation of the sympathetic nervous and renin-angiotensin systems. This reflex neurohumoral hyperactivity via endogenous vasoconstrictors/vasopressors such as angiotensin II and noradrenaline induces arterial vasoconstriction in different extrasplanchnic vascular beds (including preglomerular arteries in the kidneys). Decreased arterial pressure (i.e. low renal perfusion pressure) and preglomerular vasoconstriction are thought to play a major role in the decline of the glomerular filtration rate (GFR). Nonrandomized studies in patients with HRS have shown that the administration of a splanchnic vasoconstrictor (vasopressin analogue or α1-adrenoceptor agonist), usually combined with intravenous albumin, causes increases in arterial pressure, arterial baroreceptor uploading, decreased neurohumoral activity, decreased renal vascular resistance, and increased GFR. Randomized clinical trials have shown that treatment with a combination of the vasopressin analogue terlipressin and intravenous albumin improves renal function in patients with type 1 HRS. Vasopressor therapy with terlipressin plus intravenous albumin is the medical treatment of choice for type 1 HRS. Copyright © 2008 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]

Background: Arterial vasodilatation, which is a major factor in the pathogenesis of the hyperkinetic circulatory state and portal hypertension in cirrhosis, is due to arterial nitric oxide (NO) overproduction secondary to endothelial NO synthase (eNOS) and inducible NOS (iNOS) upregulation. However, in cirrhosis, the respective roles of eNOS and iNOS isoforms in NO overproduction are still unknown and the effect of iNOS modulation on eNOS activity and expression has not been evaluated in the systemic or splanchnic vessels. The aim of this study was to evaluate the effects of modulating aortic and superior mesenteric arteries (SMA) iNOS on arterial eNOS activity and expression in rats with cirrhosis. Methods: eNOS and iNOS protein expression and eNOS activity (assessed by its phosphorylation at serine 1177) were measured in the aortas and SMA in untreated and treated cirrhotic rats with lipopolysaccharide (LPS), N-iminoethyl-L-lysine (L-NIL), a selective iNOS inhibitor, and LPS plus L-NIL. Results: LPS administration significantly increased eNOS and iNOS protein expression and eNOS activity in the aortas of both sham-operated and cirrhotic rats. However, in SMA, LPS administration induced a decrease in eNOS protein expression and activity and an increase in iNOS protein expression. Conclusion: The results of this study may explain the worsening of the hyperdynamic state in cirrhosis during septic shock by direct LPS-induced eNOS activation in large systemic vessels, and its inhibition in concomitant small splanchnic vasculature by iNOS synthesized NO. [ABSTRACT FROM AUTHOR]

Background: FibroTest (FT) is a biomarker of liver fibrosis initially validated in patients with chronic hepatitis C (CHC). The aim was to test two hypotheses, one, that the FT diagnostic value was similar in the three other frequent fibrotic diseases: chronic hepatitis B (CHB), alcoholic liver disease (ALD) and non-alcoholic fatty liver disease (NAFLD); and the other, that the FT diagnostic value was similar for intermediate and extreme fibrosis stages. Methods: The main end points were the FT area under the ROC curves (AUROCs) for the diagnosis of bridging fibrosis (F2F3F4 vs. F0F1), standardized for the spectrum of fibrosis stages, and the comparison of FT AUROCs between adjacent stages. Two meta-analyses were performed: one combining all the published studies (random model), and one of an integrated data base combining individual data. Sensitivity analysis integrated the independency of authors, lenght of biopsy, prospective design, respect of procedures, comorbidities, and duration between biopsy and serum sampling. Results: A total of 30 studies were included which pooled 6,378 subjects with both FT and biopsy (3,501 HCV, 1,457 HBV, 267 NAFLD, 429 ALD, and 724 mixed). Individual data were analyzed in 3,282 patients. The mean standardized AUROC was 0.84 (95% CI, 0.83—0.86), without differences between causes of liver disease: HCV 0.85 (0.82—0.87), HBV 0.80 (0.77—0.84), NAFLD 0.84 (0.76—0.92), ALD 0.86 (0.80—0.92), mixed 0.85 (0.80—0.93). The AUROC for the diagnosis of the intermediate adjacent stages F2 vs. F1 (0.66; 0.63—0.68, n = 2,055) did not differ from that of the extreme stages F3 vs. F4 (0.69; 0.65—0.72, n = 817) or F1 vs. F0 (0.62; 0.59—0.65, n = 1788). Conclusion: FibroTest is an effective alternative to biopsy in patients with chronic hepatitis C and B, ALD and NAFLD. The FT diagnostic value is similar for the diagnosis of intermediate and extreme fibrosis stages. [ABSTRACT FROM AUTHOR]

The question of which colloid (albumin or synthetic colloids) used for plasma expansion following paracentesis or other complications requiring fluid loading in patients with cirrhosis remains controversial. Aims: To compare outcome and hospital-related cost in patients with cirrhosis treated with 20% human albumin with those treated with a synthetic colloid (3.5% polygeline). Methods: The primary end point was occurrence of a first liver-related complication. Results: When the trial was prematurely discontinued because of safety concerns about bovine-derived products, 30 patients were assigned to receive albumin and 38 were assigned to receive a synthetic colloid. Sixty-three patients were included for ascites removal by paracentesis and five patients for ascites removal by paracentesis and renal impairment. The median time to first liver-related complication was not significantly longer in the albumin group (20 vs. 7 days). However, the total number of liver-related complications adjusted to a 100-day period was significantly lower in the albumin group. The median hospital cost for a 30-day period was significantly lower in the albumin group (1915 euros vs. 4612 euros). Conclusions: In patients with cirrhosis and ascites, human albumin appears to be more effective in preventing liver-related complications than synthetic colloid. This may be associated with decreased hospital costs. [ABSTRACT FROM AUTHOR]

Background: Bacterial translocation, that is, extra-intestinal dissemination of gut bacteria, occurs in approximately 50% of humans and rats with cirrhosis and plays a significant role in enhanced tumor necrosis factor-α (TNF-α) production. The authors’ previous studies have indicated that prevention of bacterial translocation with norfloxacine or inhibition of TNF-α with pentoxifylline treatment decreased both the incidence and severity of hepatopulmonary syndrome by attenuating the induction of pulmonary intravascular macrophages in cirrhotic rats. In the present study the hypothesis was tested that the cirrhotic rats with bacterial translocation had higher TNF-α production, higher level of sequestration of macrophages in pulmonary vessels, and increased incidence and severity of hepatopulmonary syndrome. Methods: Rats were studied 5 weeks after common bile duct ligation or sham operation. Bacterial translocation was defined by positive mesenteric lymph node cultures. Hepatopulmonary syndrome was assessed by measurements of alveoloarterial oxygen difference (AaPO2) and intrapulmonary shunt. The TNF-α concentration in plasma was measured by ELISA. Pulmonary intravascular macrophage sequestration was assessed by lung morphometric analysis. Results: Bacterial translocation occurred in 48% of cirrhotic rats. Plasma concentrations of TNF-α and the percentage of vessels with pulmonary intravascular macrophages were higher in the cirrhotic rats with bacterial translocation. Rats with bacterial translocation also had a higher incidence (9% vs 63%, P < 0.01) and severity of hepatopulmonary syndrome, as indicated by higher levels of both AaPO2 and intrapulmonary shunt. Conclusions: These results suggest that bacterial translocation may play a role in the pathogenesis of hepatopulmonary syndrome by inducing pulmonary intravascular macrophages through TNF-α upregulation. [ABSTRACT FROM AUTHOR]

Ahloulay M, Bankir L, Lugnier C, Le Bec A, Poirel O, Moreau R, Lebrec D. Cyclic AMP-phosphodiesterases inhibitor improves sodium excretion in rats with cirrhosis and ascites.Liver International 2005: 25: 403–409.© Blackwell Munksgaard 2005The mechanisms responsible for renal dysfunction and sodium retention in cirrhosis remain unclear. Cyclic AMP (cAMP) regulates sodium reabsorption in the proximal nephron. This study investigates the role of cAMP metabolism in renal dysfunction in cirrhosis.Renal function was studied by the clearance technique in anesthetized control and cirrhotic rats with or without ascites. cAMP phosphodiesterase (PDE) activity was measured in the renal cortexin vitro. Moroever, the effects on renal function of the intravenous administration of cAMP and rolipram, a powerful and specific cAMP-PDE4 inhibitor, were evaluated.In control and in non-ascitic cirrhotic rats, cAMP administration significantly increased sodium and phosphate excretions, but did not change these excretions in cirrhotic rats with ascites. cAMP-PDE activity was higher in ascitic than in control rats (P<0.05). Rolipram infusion significantly increased sodium and phosphate excretion only in cirrhotic rats with ascites.These results suggest that increased renal cAMP-PDE activity is responsible for resistance to the natriuretic effects of cAMP in cirrhosis and plays a role in the development of ascites. [ABSTRACT FROM AUTHOR]

Moreau R, Delègue P, Pessione F, Hillaire S, Durand F, Lebrec D, Valla D-C. Clinical characteristics and outcome of patients with cirrhosis and refractory ascites.Liver International 2004: 24: 457–464.© Blackwell Munksgaard 2004In patients with cirrhosis, refractory ascites is associated with a poor prognosis and is an indication for liver transplantation. However, factors that determine prognosis remain unclear.To investigate the predictive factors of prognosis in patients with refractory ascites.Seventy-five patients with refractory ascites were followed-up for 18±13 months (mean±SD) and survival was analyzed.The 1-year probability of survival was 52%. Univariate analyses showed that older patients, hepatocellular carcinoma and diabetes, all assessed at entry, were associated with significantly increased risk ratios of death. The risk ratio of death was significantly lower in abstinent alcoholics than in patients with nonalcoholic cirrhosis. The risk ratio of death did not significantly differ between patients with nonalcoholic cirrhosis and nonabstinent alcoholics. Child–Pugh score at entry had no prognostic value. Multivariate analysis showed that older age, hepatocellular carcinoma, diabetes and abstinence were independent prognostic factors.In patients with cirrhosis and refractory ascites, older age, hepatocellular carcinoma and diabetes, but not Child–Pugh score at entry, were independent predictive factors of poor survival while abstinence was an independent predictive factor of good survival. These findings should be taken into account when deciding on liver transplantation in patients with refractory ascites. [ABSTRACT FROM AUTHOR]

Plessier A, Denninger M-H, Consigny Y, Pessione F, Francoz C, Durand F, Francque S, Bezeaud A, Chauvelot-Moachon L, Lebrec D, Valla D-C, Moreau R. Coagulation disorders in patients with cirrhosis and severe sepsis. Liver International 2003: 23: 440–448. © Blackwell Munksgaard, 2003 In patients with cirrhosis, severe sepsis may stimulate the extrinsic coagulation pathway resulting in thrombin generation and fibrin formation. To compare 23 patients with severe sepsis to 13 infected patients without severe sepsis and 18 patients without infection. Zymogen forms of clotting factors involved in the extrinsic pathway (i.e., factors VII+X, V, prothrombin), and the presence of soluble fibrin were assessed. Zymogen forms of clotting factors were significantly lower, while Child–Pugh score and the proportion of patients with soluble fibrin were higher in the severe-sepsis group than in the other groups. Decreased zymogen levels were independently correlated with an elevated Child–Pugh score and the presence of severe sepsis. In the severe-sepsis group, after adjustment for the severity of cirrhosis, decreased zymogen levels were associated with significant increases in the relative risk ratios of in-hospital death. Cirrhotic patients with severe sepsis have decreased blood levels of zymogen forms of factors VII+X, V, and prothrombin, which may be due not only to the severity of cirrhosis but also, at least in part, to the consumption of these zymogens by the extrinsic coagulation pathway. [ABSTRACT FROM AUTHOR]

Provides an overview of portal vein thrombosis in the West. Pathogenesis of the disease; Pathophysiology; Management.

Abstract Background and Aim: Hypoxemia is common in patients with cirrhosis but the natural history of this syndrome is unknown. The aim of this study was to follow a series of patients with cirrhosis and to compare patients with and without hypoxemia to determine their risk of complications and survival rate. Methods: Fifty-eight consecutive Child–Pugh C patients with cirrhosis were included and followed up for 1–18 months. Blood gas measurements and plasma endothelin levels were measured in all patients. Blood gas measurements were repeated in 34 patients. Results: Hypoxemia was present in 35 patients (60%) (alveolar-arterial oxygen (AaO2 ) gradient > 20 mmHg) but none had pulmonary symptoms. There was no significant difference in liver tests and plasma endothelin levels between hypoxemic and non-hypoxemic patients. The occurrence of variceal bleeding and survival rate was not significantly different between the two groups. The AaO 2 gradient worsened in nine patients and normalized in six of the hypoxemic patients. The AaO 2 gradient increased to more than 20 mmHg in seven non-hypoxemic patients. There was no relationship between AaO 2 gradient changes and Child–Pugh score grade changes. Conclusion: Asymptomatic hypoxemia is common in patients with severe cirrhosis but it is not a predictive factor of short-term complications or mortality. These results should be considered when deciding on liver transplantation. [ABSTRACT FROM AUTHOR]

Abstract Background and Aim: Terlipressin has been proposed to treat renal failure in patients with type 1 hepatorenal syndrome (HRS). However, the predictive factors for improved renal function and survival are unknown in patients with type 1 HRS treated with terlipressin. The aim of the present retrospective study was to investigate the predictive factors and prognosis of patients with type 1 HRS treated with terlipressin. Methods: The clinical charts of 18 consecutive patients with cirrhosis and type 1 HRS treated with terlipressin were studied. The predictive factors for improved renal function and survival were identified using univariate analyses. Results: Improved renal function, indicated by a significant decrease in serum creatinine (61 ± 4%), occurred in 11 (60%) patients. The only predictive factor for improved renal function was a Child–Pugh's score ≤13 at the time of diagnosis of HRS (P = 0.02). Fifteen patients (83%) died at 45 days and the median survival was 24 days. Of the three patients who survived, two underwent successful orthotopic liver transplantation. Three predictive factors for survival were identified: absence of a precipitating factor for HRS ( P = 0.012); improved renal function during terlipressin therapy ( P = 0.05); and a dose of terlipressin ≥3 mg/day ( P = 0.04). Conclusions: In patients with type 1 HRS treated with terlipressin, patients with improved renal function had less severe cirrhosis (Child–Pugh >10 but ≤13) than patients without. The predictive factors for survival were the absence of a precipitating factor for HRS, the terlipressin-induced improvement in renal function and a dose of terlipressin of at least 3 mg/day. These findings suggest that a randomized controlled trial investigating the effect of terlipressin on survival in patients with type 1 HRS should be performed. © 2002 Blackwell Publishing Asia Pty Ltd. [ABSTRACT FROM AUTHOR]

OBJECTIVE:Prognostic assessment of patients with alcoholic cirrhosis is still controversial. A prospective study was performed to evaluate hemodynamic values as prognostic factors of death in a group of patients with severe alcoholic cirrhosis.METHODS:From January, 1991 to February, 1993, a total of 87 admitted patients were prospectively studied. Measurements of the hepatic venous pressure gradient and cardiac output were performed in all patients. The mean follow-up was 35 months (range 1–76 months).RESULTS:During this period, 56 patients (63% at 5 yr) died. The hepatic venous pressure gradient and cardiac output were not significantly different between the two groups. Using univariate analysis, only age and bilirubin concentration were different between those patients who lived and those who died. Cox regression analysis showed that age, encephalopathy, bilirubin concentration, prothrombin time, and Child-Pugh score were the only prognostic factors.CONCLUSION:Measurement of the hepatic venous pressure gradient is not helpful in the prognostic assessment in a select group of patients with severe alcoholic cirrhosis. [Copyright &y& Elsevier]

In patients with cirrhosis, discrepant findings have been reported on the evolution of pulmonary hemodynamics and gas exchange after liver transplantation. The aim of this study was to evaluate the effects of liver transplantation on pulmonary and systemic hemodynamics and gas exchange in patients transplanted for cirrhosis. Forty-three patients with cirrhosis underwent hemodynamic investigations before and one year after liver transplantation. Mean pulmonary arterial pressures did not significantly change after transplantation (from 17 +/- 4 to 17 +/- 3 mm Hg) whereas pulmonary vascular resistance significantly increased by 62%. Cardiac index significantly decreased by 20%. PaO2 did not change significantly after transplantation (from 88.8 +/- 13.9 to 88.5 +/- 12.1 mm Hg) and PaCO2 significantly increased by 16%. In conclusion, liver transplantation has no effect on pulmonary pressures but normalizes pulmonary vascular resistance in patients with cirrhosis without pulmonary hypertension. Moreover, it has no major effect on gas exchange in patients with cirrhosis without hypoxemia. [ABSTRACT FROM AUTHOR]

Abstract Background and Aims: Cirrhosis is associated with a hyperdynamic syndrome and arterial vasodilation that is related to nitric oxide (NO) synthase 3 overactivity. Septic shock is frequently associated with cirrhosis and with a vascular induction of NO synthase 2. The aims of this study were to compare the effects of lipopolysaccharide (LPS) in normal and cirrhotic rats, and to test the effects of a-non-steroidal anti-inflammatory drug (NSAID) coupled with a (NO) donor. Methods: Cirrhotic rats received NO-flurbiprofen, flurbiprofen or vehicle followed by LPS or placebo 15 min later. The heart rate and mean arterial pressure of rats were monitered for 5 h. Thoracic aortic rings were removed and contracted with the use of norepinephrine. Nitric oxide synthase activity was measured in the aorta and stomach of cirrhotic rats. Results: Arterial pressure decreased in cirrhotic rats in the vehicle/LPS and flurbiprofen/LPS groups. After LPS administration, the heart rate of rats increased in all groups. In the aortic rings, LPS induced hyporeactivity to norepinephrine in all groups except the NO-flurbiprofen group. This hyporeactivity was abolished after preincubation with Nw-nitro-L-arginine (L-NNA). Nw-nitro-L-arginine had no effect on norepinephrine-induced vasoconstriction in the NO-flurbiprofen/LPS group. Nitric oxide synthase 2 activity in the stomach and aorta of cirrhotic rats was increased in each group except in the NO-flurbiprofen group after LPS administration. Pretreatment with NO–NSAID prevented aortic hyporeactivity to norepinephrine in cirrhotic rats treated with LPS as it probably inhibited the NO synthase 2 induction. Conclusions: These findings suggest that NO-flurbiprofen has a beneficial hemodynamic effect in cirrhotic rats and may help to prevent LPS aortic hyporeactivity. [ABSTRACT FROM AUTHOR]

Aims: In cirrhosis, the effects of selective activation of atrial natriuretic peptide (ANP) R2-receptors on haemodynamics, endogenous ANP (ANP1–28) and sodium excretion are unknown. The aim of the present study was to examine the effects of selective activation of ANP-R2 receptors by ANP4–23 (a ring-deleted analogue of endogenous ANP) on haemodynamics, plasma ANP1–28 concentrations and urinary sodium excretion in conscious cirrhotic and normal rats. Methods: Haemodynamics and sodium excretion were measured prior to and following administration of ANP4–23. Plasma ANP1–28 concentrations were also measured. Results: In cirrhotic rats, ANP4–23 significantly decreased portal pressure and tributary blood flow by 15% and 25% respectively but significantly increased portal territory vascular resistance by 30%. Systemic and renal haemodynamics were not altered by ANP4–23. In normal rats, ANP4–23 did not significantly change splanchnic, renal and systemic haemodynamics. In both groups of rats, ANP4–23 increased plasma ANP1–28 concentrations but did not change sodium excretion. Conclusions: ANP4–23 administration induced splanchnic vasoconstriction in cirrhotic but not in normal rats. ANP4–23-elicited vasoconstriction caused a portal hypotensive effect in cirrhotic rats. Finally, in both groups, ANP4–23 caused an increase in plasma ANP1–28 concentrations but did not increase sodium excretion. [ABSTRACT FROM AUTHOR]

A substance which increases the entry of extracellular calcium into arterial smooth muscle may decrease cirrhosis-induced vasodilation. The aim of the present study was to measure the effects of the L-type Ca2+ channel activator, Bay K 8644, on the haemodynamics of rats with cirrhosis. Vascular reactivity to this substance was also investigated. Splanchnic and systemic haemodynamic responses to Bay K 8644 (50 μg/kg) were measured in cirrhotic and normal rats. Contraction induced by 0.1 μmol/L Bay K 8644 was measured in arterial rings (aorta and superior mesenteric artery) from cirrhotic and normal rats. In cirrhotic rats, Bay K 8644 significantly decreased portal pressure (15%) and portal tributary blood flow (24%), significantly increased portal territory vascular resistance (54%) and did not significantly change hepatocollateral vascular resistance. Bay K 8644 significantly increased arterial pressure (7%) and systemic vascular resistance (24%) and did not change the cardiac index. In normal rats, Bay K 8644 significantly increased vascular resistance (150%) in portal, hepatocollateral and systemic territories and significantly decreased the cardiac index (44%). Changes in portal territory, hepatocollateral and systemic vascular resistances were significantly less marked in cirrhotic than in normal rats. In rings from the aorta and superior mesenteric artery, Bay K 8644-induced contraction was significantly lower in cirrhotic than in normal rats. In conclusion, in rats with cirrhosis, Bay K 8644 administration reduced vasodilation in splanchnic and systemic arteries and did not affect hepatocollateral vascular resistance. The Bay K 8644-induced reduction in splanchnic vasodilation caused a decrease in portal hypertension. This study also shows that Bay K 8644-induced vascular contraction was less marked in cirrhotic than in normal rats, in systemic and splanchnic vascular beds. [ABSTRACT FROM AUTHOR]

Aims/Background: Vascular hyporesponsiveness to sympathomimetic stimulation occurs in jaundice. Recently, we reported that this vascular adrenergic hyporesponsiveness was associated with the loss of reactivity of vascular α1-adrenoceptors. This study examines the possibility that the vascular adrenergic hyporesponsiveness is due to down-regulation of vascular α1-adrenoceptors. Methods: This question was addressed by measuring the changes in the plasma norepinephrine (NE) and epinephrine (E) concentrations, determined by high performance liquid chromatography, and the affinity and number of α1-adrenoceptors determined by a competitive antagonist radioligand binding assay in vascular smooth muscle membranes prepared from 3-day bile duct ligated (BDL) rats. The results were compared to data obtained from 3-day bile duct manipulated (sham-operated; SO) and control (C) rats. Results: Compared to C and SO rats, the plasma concentrations of NE and E in the BDL rats were significantly elevated reflecting increased sympathetic nervous system activity. BDL did not change either the affinity or the number of vascular α1-adrenoceptors. Conclusions: Since the affinity and number of vascular α1-adrenoceptors were unchanged in the face of elevated plasma concentrations of catecholamines in the BDL rats, we have concluded that down-regulation of vascular α1-adrenoceptors does not account for the vascular adrenergic hyporesponsiveness in experimental cholestasis. [ABSTRACT FROM AUTHOR]